GB2058066A

GB2058066A - 6h-1,3,4-thiadiazine-2-amines

Info

Publication number: GB2058066A
Application number: GB8028272A
Authority: GB
Original assignee: Richardson Merrell Inc
Current assignee: Richardson Vicks Inc
Priority date: 1979-09-04
Filing date: 1980-09-02
Publication date: 1981-04-08
Also published as: NO802593L; AT375356B; IT1145385B; NO152697C; NL8004900A; DK149364B; IE50093B1; US4289767A; JPS5640676A; PH16660A; DE3031703A1; AU6171780A; IE801686L; ATA439880A; ZA805000B; BE885039A; SE434944B; NO152697B; AU531585B2; DE3031703C2

Description

1 GB 2 058 066 A 1

SPECIFICATION

Thiadiazine-2-amines The present invention relates to 5-(chlo rophenyi)-6H-1,3,4-th iadiazine- 2-a mines, having anticonvulsant and 5 anxiolytic activity.

As a general class, 5-(optionally substituted phenyi)-6H-1,3,4thiadiazine-2-amines are known as chemical intermediates. See, for example, Japanese Patents 74-110,696,74-110,697 and 74-100,080. Many individual species related to the compounds of this invention are also known as chemical intermediates. See, for example:

4. 5. 6. 7. 8.

9.

10. 11. 12. 13. 25 14. 15. 16. 17. 18. 30 19. 20.

1. Japanese Patent 75 37651; 2. McLean et al, J. Chem. Soc. 1937,556-9; 3. Avramovici, Analele stiint. univ.---Al. 1. Cuz&' lasi, Sect. 1 (Mat. Fiz. , chim.). (N.S.) 1, 315-319 (1955).

CA51:10541; Beyer et a], Justus Liebigs Ann. Chem. 741,45-54 (1970; Japanese Patent 74-110,696; Japanese Patent 74-110,697; Bose, Quart. J. Indian Chem. Soc. 1, 51-62 (1924). Beyer et al, Chem. Ber. 89,107-14 (1956); Japanese Patent 74-88,889; Japanese Patent 74-100,080; Bose, Quart. J. Ind. Chem. Soc. 2, 95-114 (1925); Bose et al. J. Indian Chem. Soc. 7,733-9 (1930); Bulka et al, Z. Chem. 1502),482 (1965); Schmidt et al, Tetrahedron Lett. 1975 (1), 33-6; Beyer, Quart. Rep. Suffur Chem. 5(3), 177-89 (1970); Saraswathi et al, Indian J. Chem. 10020151-4 (1972); Hampel, Z. Cham. 9(2),61-2 (1969); Pfeiffer et al, Z. Chem. 17(6), 218-20 (1977); Pfeiffer et al, Synthesis 1977(7),485-6; and Pfeiffer et al, Synthesis 1977(3), 196-8.

Certain species are further known as flame retardants (Japanese Patent 745439).

Moreover, some 2-amino-1,3,4-thiadiazines are generally known to have antiviral, anflinflammatory and analgesic activity (Japanese Patent 7488889). Additionally, many individual species related in structure to the compounds of this invention are disclosed in this same reference. Some species have been found ineffective as vitamin B substitutes (Robbins et al, Proc. Nati. Acad. Sci. U.S. 24,141-5 (1938) and antitubercular agents (Ban., J. Pharm. Soc. Japan 73, 533-7 (1953) and Bilinski et al, Bull. Acad. Polon. Sci., Ser. Sci. Chim. 13(6), 393-6 (1965)).

Other compounds having significantly different structures are also known to possess pharmacological activity.

4-m ethyl -4H-5,6-d i hyd ro-1,3,4-th iad i azi n-2-a m i nes are known to be CNS active (U.S. Patent 3,428,631 and Trepanier et al, J. Med. Chem. 10(6), 1085-7 (1967W Additionally, 3- substituted 1,2-dihydro-1,3,4-thiadiazin 2-imines are known as slow cure accelerators for rubber (U.S. Patent 2, 871,237).

The 5-membered ring-containing 2-amino-1,3,4-thiadiazoles are known to possess CNS depressant activity (Maffii et al, 11 Farmaco (Pavia) Ed. Sci. 13, 187-217 (1958); Great Britain Patent 815,188; W. German 45 Patent 2,212,245 (or Great Britain 1,380,136); U.S. Patent Number 3,965, 110; U.S. Patent Number 4,054,665; U.S. Patent Number 3,919,428; and U.S. Patent Number 3,992,396) and anti hypertensive activity (U.S. Patent Number 3,746,716).

These 5-membered ring-containing 1,3,4-thiadiazole-2-amines are a class of compounds treated by the prior art as distinct from the 6-membered ring-containing 1,3,4- thiadiazin-2-amines. However, the preparation of both types of compounds are reported together by Rao, Khim. Geterotsiki. Soedin. 1977(3), 291-310, as does Klosa, Arch. Pharm. 287,12-14 (1954). In the latter reference, the compounds are reported as potential, but untested, tuberculostatics. Compounds of both types are also disclosed in Japanese Patent 74 5439 a s f i re reta rd a nts.

Compounds of Formula 1 S NHR R, cl I 2 GB 2 058 066 A 2 wherein R is H, C1-5 or 7-straight or branched chain alkyl or ally[ and R1 is H or Cl, and the pharmaceutical ly acceptable acid addition salts thereof.

Illustrative examples of straight or branched chain Cl-5 alkyl groups mentioned above in all instances in describing the group R include, for example, methyl, ethyl, n-propyi, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopenty], neopenty], etc. Illustrative examples of straight or branched chain C7 alkyl groups which R may represent as used herein include, for example, n-heptyl, isoheptyl, etc.

Pharmaceutically acceptable acid addition salts of the compounds of Formula 1 include those of any suitable inorganic or organic acid. Suitable inorganic acids are, for example, hydrochloric, hydrobromic, sulfuric or phosphoric acid. Suitable organic acids are, for example, carboxylic acids, such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic and 2-phenoxybenzoic, or sulfonic acids such as, for example, methanesulfonic and 2- hydroxyethane-suifonic acid.

Of the compounds of Formula 1, those wherein R, is Cl, preferably 4-Cl, especially those wherein also R is C1-5 straight or branched chain alkyl or alIVI, are preferred. Thus, preferred compounds include 5-(2,4-dich lorophenyl)-N-methyl-6H-1,3,4-thiadiazi n-2-a mine, 5-(2,4dichlorophenyi)-N-ethyi-6H-1,3,4thiadiazin-2-amine, 5-(2,4dichlorophenyl)-N-propyi-6H-1,3,4-thiadiazin-2-amine, N-butyi-5-(2, 4dichlorophenyi)-6H-1,3,4-thiadiazin-2-amine and 5-(2,4-dichlorophenyi)-Npentyl-6H-1,3,4-thiadiazin-2amine, 5-(2,4-D-dichlorophenyi)-N-2-propenyi6H-1,3,4-thiadiazin-2-amine and their acid addition salts.

Illustrative examples of compounds of this invention include, for example, 5-(2,4-dichlorophenyi)-N- pentyi-6H-1,3,4-thiadiazin-2-amine, N-buty]-5-(2,4-dichlorophenyi)-6H-1,3, 4-thiadiazin-2-amine, 5-(2,4dichlorophenyi)-N-propyi-6H-1,3,4-thiadiazin- 2-amine, 5-(2,5-dichlorophenyi)-N-methyi-6H-1,3,4-thiadiazin2-amine, 5-(2, 4-dichlorophenyi)-N-ethyi-6H-1,3,4-thiadiazin-2-amine, 5-(2-chlorophenyi)N-methyi-6H-1,3,4thiadiazin-2-amine, 5-(2,4-dichlorophenyi)-N-methyl-6H-1, 3,4-thiadiazin-2-amine and 5-(2,4-dichlorophenyi)6H-1,3,4-thiadiazin-2amine, 5-(2,4-dichlorophenyi)-N-2-propenyi-6H-1,3,4-thiadiazin-2-amine, 5(2,4- dichlorophenyl)-N-heptyi-6H-1,3,4-thiadiazin-2-amine and the acid addition salts of each.

The compounds of this invention are useful as anticonvulsant and anxiolytic agents and, thus, as tranquilizers. These compounds can be administered to warm-blooded animals, mammals, rats, mice, dogs, cats, horses, pigs, cows, sheep, and humans. As used herein, the term -patientis intended to mean the animal or mammal being treated.

The pharmacological activities of the compounds of the compounds of this invnetion maybe illustrated by 30 their effectiveness in standard pharmacological screening tests. For example, their anticonvulsant and anxiolytic efficacy may be demonstrated by their inhibition of clonic seizures induced by injection of metrazole in mice (Metrazole Antagonism Test).

Especially advantageous aspects of the compounds of this invention include a favorable spectrum of activity, low addiction liability and abuse potential, and a favorable dissociation between desired activity and 35 unwanted side effects such as induction of sedation, The compounds of this invention can be administered orally or parenterally either alone or in the form of a pharmaceutical preparation. Pharmaceutical preparations containing conventional pharmaceutical carriers and as active ingredients compounds of this invention can be employed in unit dosage forms such as solids, for example, tablets, capsules, and pills, or liquid solutions, suspensions, or emulsions for oral and parenteral administration. The dosage unit administered can be any anticonvulsant or anxiolytic effective amount. The quantity of compound administered can vary over a wide range to provide from about 30 to about 50 mg kg of body weight of the patient per day, to achieve the desired effect. Unit doses can contain about 5-500 mg of a compound of Formula 1 and may be administered, for example, from 1 to 4 times daily.

The compounds of Formula 1 are prepared by reacting a phenacyl halide of the formula i 2 CO-CHzX R1 Cl with a 4-substituted thiosemicarbazide of the formula H S H H2WN-C-N-R wherein X is Cl or Br and R, and R, are as hereinbefore defined. The reaction is generally conducted in the 60 presence of a solvent, e.g., a lower alkanol, such as, methanol, ethanol, isopropanol, n-propanol, n-butanol and the like, preferably methanol. The reaction time may vary from about 15 minutes to about 1 hour, preferably about 30 minutes, depending upon the reactants, the solvent and the reaction temperature which may vary from about 60-C to about WC, preferably around WC. The product is generally worked-up by permitting the reaction mixture to cool and then concentrating it in vacuo. The resultant residue is ri 3 GB 2 058 066 A 3 recrystallized from an appropriate solvent, e.g., a mixture of a lower alkanol with, e.g., acetone, butanone or ethyl acetate, e.g., methanol/acetone or methanol/ethyl acetate, producing the compound of Formula 1 as its hydrohalide salt.

Both the phenacyl halide and the 4-substituted thiosemicarbazide which are employed as starting materials in the preparation of the compounds of Formula 1 are either commercially available or, when 5 unavailable, are very readily preparable by standard chemical reactions which are well-known to those of ordinary skill in the art. For example, the phenacyl halides may be prepared by halogenating the corresponding methyl chlorophenyl ketone using a sulfuryl halide, e.g., sulfuryl chloride, in e.g., acetic acid, e.g., to prepare the corresponding phenacyl chloride; or by reacting the corresponding chlorobenzene with a haloacetyl halide, e.g., chloroacetyl chloride via a Friedel Crafts reaction using an aluminium trichloride 10 catalyst, e.g., to prepare the corresponding phenacyl chloride. The 4- subsituted thiosemicarbazicles may be prepared by conventionally reacting the appropriate substituted isothiocyanate with hydrazine in the presence, e.g., of diethyl ether.

The following examples are illustrative of the invention.

EXAMPLE 1

5-(2,4-Dichlorophenyl)-N-pentyl-dH 1,3,4-thiadiazin-2-amine monohydrochloride 4.84 g (.03 mole) of 4-N-pentyi-thiosemicarbazide and 6.70 g (.03 mole) of (2,4-dichlorophen)acyl chloride are heated and stirred at reflux (65'C) in 175 mi of methanol for 30 minutes. At this time, the solvent is removed in vacuo. The residue is dissolved in methanol, warmed and then diluted with acetone.

Subsequently, it is concentrated to a volume of approximately 200 mi. 6.7 9 of 5-(2,4-dichlorophenyi)-N penty]-6H-1,3,4-thiadiazin-2-amine monohydrochloride precipitate out as a white solid. m.p. 171-1173'C. The solid is subsequently dried under high vacuum at 780C.

is EXAMPLE 2

N-Butyl-5-(2,4-dichlorophenyl)-H- 1,3,4-thiadiazin-2-amine monohydrochloride Utilizing the procedures of Example 1, 4.47 g (.014 mole) of (2,4- dichlorophen)acyl chloride and 2.66 9 (.014 mole) of 4-N-butyl thiosernicarbazicle are reacted, except that 150 m[ of methanol are used as the solvent.

The resultant precipitate is recrystallized from methanollethyl acetate yielding 3.98 g of a white solid, N-butyi-5-(2,4-dichlorophenyi)-6H-1,3,4-thiadiazin-2-amine monohydrochloride, m.p. 180-182'C. The solid is 30 subsequently dried at 7WC under high vacuum.

EXAMPLES 3-7

Utilizing the conditions of Example 2, the following compounds (starting from the mentioned reactants) were prepared:

EXAMPLE 3 - 5-(2,4-dichlorophenyl)-N-propy]-6H-1,3,4-thiadiazin-2-amine monohydrochloride (6.4 g) (from (2,4-dichlorophen)acyl chloride (6.70 g -.03 mole) and 4-n-propyi- thiosemicarbazide (3.99 g -.03 mole)), m.p. 184-185OC; EXAMPLE 4 - 5-(2,4-dich lorophenyl)-N-methyl-6H-1,3,4-thiadiazi n-2-a mine monohydrochloride (from (2,5-dichlorophen)acyl chloride (5.58 g) and 4-methyi-thiosemicarbazide (2.63 g)). m.p. 193-194.5'C.

EXAMPLE 5 - 5-(2,4-dich lorophenyi)-N-ethyl-6H-1,3,4-thiadiazin-2-a mine monohydrochloride (6.5 g) (from (2,4-dichlorophen)acyl chloride (9.3 g -.04 mole) and 4-methyl- thiosemicarbazide (4.77 g -.04 mole); in 200 mi of methanol). m.p. 197-198'C.

EXAMPLE 6 - 5-(2,4-dichlorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride (2.9 g) (from (2-chlorophen)acyl chloride (4.40 g -.023 mole) and 4-methyl- thiosemicarbazide (2.42 g -.023 mole); in 5 m] of methanol). m.p. 173.5-174.5'C; EXAMPLE 7 5-(2,4-dichlorophenyi)-N-methyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride (from (2,4-dichlorophen)acyl chloride (11.17 9 (.05 mole) and 4-methyi- thiosemicarbazide (.05 mole); in 200 mI of methanol, employing an additional recrystallization from methanol/ethyl acetate). m.p. 195'C.

so EXAMPLE 8 5-(2,4-Dichlorophenyl)-H- 1,3,4-thiadiazin-2-amine hydrochloride - 11.17 g (.05 mole) of (2,4-dichlorophen)acyl chloride and 4.36 g (.05 mole) of thiosemicarbazide are stirred and heated in methanol (250 mi) at reflux (65'C) for 30 minutes. The resultant suspension is allowed to cool and is filtered to yield a first crop of 4.56 g of 5-(2,4-dichlorophenyl)- 6H1,3,4-thiadiazine-2-amine hydrochloride. The reaction mixture is then diluted with ethyl acetate and concentrated in a steam bath giving 6.2 g of the same compound. The products are combined and recrystallized from methanol/ethyl acetate. m.p. 170-1720C.

EXAMPLE 9 5-(2,4-Dichlorophenyl)-N-2-propenyl6H- 1,3,4-thiadiazin-2-amine monohydrochloride 3.93 g (.03 mole) of 4-aiiyl-thiosemicarbazide and 7.00 g (.03 mole) of (2,4-dichlorophen)acyl chloride are reacted in accordance with the conditions of Example 1. Recrystallization from methanol/methyl acetate produces 8 9 of 5-(2,4-dichlorophenyl)-N-2-propenyi-6H-1,3,4-thiadiazin-2- amine. m.p. 188-189'C.

4 GB 2 058 066 A 4 EXAMPLE 10

5-(2,4-Dichlorophenyl)-N-heptyl-H- 1,3,4-thiadiazin-2-amine monohydrochloride 3.78 g (.02 mole) of 4-n-heptyi-thiosemicarbazide and 4.67 9 (.02 mole) of (2,4-dichlorophen)acyl chloride are reacted analogously to Example 1. After recrystallization from methanollmethyl acetate, 5.2 g of 5-(2,4-dichlorophenyi)-N-heptyi-6H-1,3,4-thiadiazin-2-amine monohydrochloride are produced. m.p. 175- 5 1770C.

i -1 EXAMPLE 11

5-(2,4-Dichlorophenyl)-N-methyl-H- 1,3,4-thiadiazin-2-amine monohydrochloride 11.17 g of 2,4-dichlorophenacyl chloride and 5.775 g of 4-methyl- thiosemicarbazide are reacted in 200 mi 10 of methanol at refluxfor 30 minutes. The solution is allowed to cool to room temperature and is then concentrated. The residue is recrystallized twice from methanollethyl acetate and dried at 65'C under high vacuum to produce 5-(2,4-dichlorophenyi)-N-methyl-6H-1,3,4-thiadiazin-2- amine monohydrochloride, m.p.

1950C.

The following Examples illustrate compositions of the invention. The active ingredient in each case is the 15 compound of Example 11.

EXAMPLE 12

Parts by weight 20 Active ingredient 100.0 Wheat starch 15.0 Lactose 33.5 Magnesium stearate 1.5 25 A portion of the wheat starch is used to make a granulated starch paste which, togetherwith the remainder of the wheat starch and the lactose, is granulated, screehed and mixed with the active ingredient and the magnesium stearate. The mixture is compressed into tablets weighing 150 mg each.

EXAMPLE 13

Acomposition is prepared by dissolving 100 parts by weight of the active ingredient and sufficient sodium chloride in 20 parts by volume of water for injection to render the solution isotonic. The composition may be dispensed in a single ampoule containing 100 mg of the active ingredient for multiple dosages or in 20 35- ampoules for single dosages. The composition may be administered parenterally by injection.

EXAMPLE 14

A composition is prepared by passing 200 parts by weight of the active ingredient and 35 parts byweight of talc, both as dry powders, through a fine mesh screen and mixing them well. The powder mixture is then filled into No. 0 hard gelatin capsules at a net fill of 235 mg per capsule.

EXAMPLE 15 parts by weight of the active ingredient are blended with 130 parts by weight of corn starch. 20 parts by volume of liquid glucose are then added with thorough kneading to form a plastic mass from which pills are cut and formed.

The compounds and compositions of the Examples can be administered as anti-convulsants for the treatment of, e.g., status epilepticus, severe recurrent convulsive, petit mal, grand mal or psychomotor seizures, or as anioxylic agents to ameliorate the anxiety, tension, agitation and irritability associated with psychoneurotic reaction, psychophysiological reaction or personality disorder, or the anxiety associated with pathological depression and with alcohol withdrawal.

Claims

1. A compound of the formula 5Q SYNHR I N R, N cl GB 2 058 066 A 5 wherein R is hydrogen, C1.5 alkyl, C7 alkyl or allyl and R, is hydrogen or chlorine; or a pharmaceutically acceptable acid addition salt thereof.

2. A compound as claimed in Claim 1 wherein R, is 4-Cl.

3. A compound as claimed in Claim 1 or Claim 2 wherein R is C1.5.

4. 5-(2,4-Dichlorophenyi)-N-methyi-6H-1,3,4-thiadiazin-2-amine monohydrochloride.

5. 5-(2,4-Dichlorophenyi)-N-(2-propenyl)-6H-1,3,4-thiadiazin-2-amine.

6. A compound as claimed in Claim 1 substantially as described in any of Examples 1 to 11.

7. A pharmaceutical composition comprising a compound as claimed in any preceding Claim in association with pharmaceutical ly acceptable carrier.

8. A composition according to Claim 7 in unit dosage form and comprising from 5to 500 mg. of the 10 compound per unit dosage.

9. A composition according to Claim 7 substantially as described in any of Examples 12 to 15.

10. A process for preparing a compound as claimed in Claim 1, which comprises reacting a phenacyl halide of the formula CO-CH2X R1 cl wherein R, is as defined in Claim 1 and X is chlorine or bromine, with a thiosemicarbazide of the formula 112N-NH-CS-NHR and R is as defined in Claim 1, and, if desired, reacting the resultant hydrohalide salt with a base.

Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon, Surrey, 1981. Published by The Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.